The goal of this R01 application is to investigate the relationships among late-life depression (LLD), cognitive impairment and progressive neurodegeneration with two imaging approaches: a novel PET ligand (Pittsburgh Compound-B; PiB) that binds to amyloid and volumetric MRI of white matter hyperintensities (WMH). The guiding hypothesis is that individuals who develop LLD have evolving cognitive impairments as a consequence of distinct underlying neuropathologic changes that frequently are expressed as Mild Cognitive Impairment (MCI). Amyloid and WMH are major neuropathologic features that lower brain reserve capacity, and in turn, increase risk of expressing clinical Alzheimer's disease. To pursue this goal, using the joint infrastructure of the University of Pittsburgh's Advanced Center for Intervention and Services Research for Late-Life Mood Disorders (MH071944) and the Alzheimer's Disease Research Center (AG05133), individuals with remitted depression will undergo PiB-PET imaging for amyloid pathology and MRI to determine WMH volume. We will study 100 remitted depressed subjects with a range of cognitive classifications (50 cognitively normal, 50 MCI) and follow them for 3 years with longitudinal clinical, cognitive and laboratory data collection through Dr. Butters' R01 (MH072947; Pathways Linking Late-Life Depression to MCI & Dementia). WMH and PiB-PET data from these subjects will be compared with similar data on 25 never-depressed non-amnestic MCI subjects gathered through the proposed research along with 75 never-depressed subjects with a range of cognitive classifications (50 cognitively normal, 25 amnestic MCI), collected under the auspices of two other funded awards (Program Project Grant AG025204 In Vivo PiB-PET Amyloid Imaging: Normals, MCI & Dementia and MERIT Award AG025516 Brain Amyloid and Cognition in Normal Elderly). We will test a series of linked hypotheses that postulate the neuropathologic substrates of some of the pathways by which elderly, depressed patients develop cognitive impairment and lead some to Alzheimer's disease.